1. Field of the Invention
The present invention relates to pharmaceutically and storage-stable compositions of nicorandil comprising suspensions or dispersions of the active nicorandil agent in linear dimethyl polysiloxanes of low and medium density (dimethicone or simethicone), and, more especially, to hard and soft gelatin capsules charged with such formulations and to the pharmaceutical use of same as coronary vasodilations.
2. Description of the Prior Art
Nicorandil, the nitrate ester of N-(2-hydroxyethyl)nicotinamide, is a known coronary vasodilator, exerting a combined action suppressing coronary vasoconstriction and an inhibitory action on the coronary channels of calcium ions, as is evidenced by the considerable clinical data reported in the literature.
In the solid crystalline state, nicorandil is stable under conditions of extreme dryness, but when it is exposed, although for short periods of time and at room temperature, even at low humidity levels, a considerable instability ensues. The hydrolysis of nicorandil is catalyzed by three factors, each influencing the others, namely, the increased percentage of moisture in the product in powder state, the temperature and the storage period.
The progressive degradation of nicorandil entails the hydrolysis of the inorganic ester contained in the molecule, with the consequent liberation of nitric acid and of N-(2-hydroxyethyl)nicotinamide, a compound that is not pharmacologically active at the considered dosages, as evidenced by the substantial decrease in the content of the active ingredient and, therefore, of the pharmacological activity.
The degradation of nicorandil in the presence of water is so rapid that in aqueous solution at 5%, the product loses, at 60.degree. C. and at pH 7 in only 12 hours, almost 20% of its titer. To the contrary, the powder in the dry state and under the same conditions of temperature, does not exhibit, during the same period, appreciable such quali-quantitative variations.
The same disadvantages and drawbacks reported for the raw material nicorandil are evidenced, albeit with more reduced intensity, during the preparation of conventional oral pharmaceutical forms (tablets), but the aforesaid phenomenon of degradation attains alarming levels during the subsequent storage periods.
The adoption of alternative techniques for the production of conventional tablets of nicorandil, containing variable amounts of saturated higher fatty acids, or of the inorganic salts thereof, or saturated higher alcohols (having a waxy or solid consistency at ambient temperatures), has provided slight improvements; however, the stability of nicorandil, when formulated in tablets, remains relatively precarious and unsatisfactory.
Moreover, the friction between the crystals of the product during the compression thereof, which occurs during the manufacture of the aforementioned preparations, has been described as a possible reason for the rupture of the crystals of nicorandil and of the consequent increased instability. This is indicated by Iida Yoshimitsu in European patent application No. 87/100,549.2 (publication 0 230 932 A2).
The use of completely moistureproof materials for the packaging of the tablets proves not only relatively expensive, but also insufficient to prevent the absorption of moisture and, therefore, to avoid the known degradation mechanisms of nicorandil therein contained, once the packaging of the pharmaceutical is opened.
In consideration of the clinico-therapeutic importance to maintain adequate dosages of nicorandil, when formulated in the adopted pharmaceutical forms, during periods of normal storage, specific studies have been conducted to develop improved formulations of nicorandil, which would be stable for an adequate period of time, thus not easily degradable, compatible with the excipients used for the formulation and, finally, preservable in conventional packaging materials, such as small glass or plastic bottles having screw caps, blister packaging or strips fabricated from thermosealed coupled foils of aluminum and copolymers.
During such research and the various attempts to provide stable preparations of nicorandil, the product has been suspended in variable amounts of triglycerides of aliphatic acids, saturated or unsaturated, having short and extended chains (from C-4 to C-12), linear or branched, monohydroxylated or not, or in variable amounts of polyglycolized glycerides of aliphatic saturated or unsaturated fatty acids, having medium-long chains (from C-8 to C-22), linear or branched, monohydroxylated or not, or in mixtures of variable amounts of the above glycerides and polyglycolized glycerides, the above vehicles being in a liquid or semi-solid state at ambient temperatures.
The above dispersions have been used to fill hard gelatin capsules (preferably having a sealing band) or soft gelatin capsules and the resulting pharmaceutical dosage forms showed an appreciable increase of stability. Moreover, this particular preparative technique avoids the compression of the active ingredient which, as above indicated, is a possible cause of the instability of the nicorandil when it is compressed. The concentrations of nicorandil in these compositions may vary in a percentage ranging from 1% to 50%. The indicated triglycerides may be individual compounds or mixtures thereof in variable proportions of conventional esters well known to this art, having the following general formula: ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are the residues of aliphatic fatty acids, typically C-4 to C-12 in length, optionally unsaturated and typically comprising from 1 to 6 double bonds, or optical, position or other isomers thereof. The polyglycolized glycerides are mixtures of esters, in different proportions, of conventional compounds, well known to this art, such esters having the following H.L.B. (Hydrophilic-Lipophilic-Balance) values:
______________________________________ H.L.B. values ______________________________________ Triglycerides from 1 to 2 Diglycerides from 2 to 3 Monoglycerides from 3 to 4 Diesters of polyethylene glycol from 6 to 15 Monoesters of polyethylene glycol from 10 to 17 ______________________________________
wherein the proportion of the five ingredients are characterized by the composition of the reaction mixture. The numbers of amphophily are expressed as H.L.B. (Hydrophilic-Lipophilic-Balance) values (from 1 to 17). The principal aliphatic acids most commonly esterified with the medium chain triglycerides (from C-8 to C-12) and with the saturated polyglycolized glycerides, are, preferably, selected from among the saturated fatty acids, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid, from among the unsaturated fatty acids, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid and linolenic acid, from among the branched acids, isostearic acid, and from among the monohydroxylated, ricinoleic acid.
The stability studies in respect of the abovedescribed formulations of nicorandil in any event evidenced that the samples stored at temperatures of about 40.degree. C. developed, after an interval of some weeks, a considerable decrease in the assay of the active ingredient nicorandil. This phenomenon has been actively studied and it has been determined that nicorandil interacts with the triglycerides of the fatty acids, saturated or unsaturated, having short-medium chain (from C-4 to C-12), linear or branched, monohydroxylated or not, and/or with the polyglycolized glycerides of aliphatic fatty acids, having medium-long chain (from C-8 to C-22), saturated or unsaturated, linear or branched, monohydroxylated or not, by virtue of a transesterification which effects the hydrolysis of nicorandil with formation of different esters of N-(2-hydroxyethyl)nicotinamide (primary aminoalcohol) with one or more fatty acids resulting from the triglyceride and/or from the polyglycolized glyceride (compounds definitely not active pharmacologically) and the simultaneous substitution of the fatty acid with nitric acid, also emanating from the nicorandil. This phenomenon is determined by high pressure liquid chromatography, whereby it is possible to determine, as soon as the transesterification of the nicorandil occurs, multiple peaks corresponding to the various resulting compounds, having different retention times which are much greater than nicorandil itself. Contrariwise, Iida Yoshimitsu, in European patent application No. 87/100,549.2 (publication 0 230 932 A2) describes formulations of nicorandil tablets, the excipients in which comprise considerable amounts of long-chain aliphatic saturated acids, or of the inorganic salts thereof, or higher aliphatic saturated alcohols, solid at ambient temperatures, optionally including a certain amount of a unique organic acid. The dissolution profile of these formulations containing only nicorandil with higher aliphatic saturated acids or higher saturated alcohols, also admixed with other conventional excipients, which only exert the function of a support, does not prove to be particularly satisfactory and, with a view towards enhancing the dissolution profile of the tablet, it is also described to include a deaggregating agent in the subject compositions or, preferably, an organic acid.
Despite the efforts to control the moisture content below the normal (3-5%), such tablets of nicorandil showed a certain instability, which is evidenced also in this case with a decrease in the assay of nicorandil during normal storage periods.
Furthermore, insufficient dissolution of the aforesaid tablets may be a disadvantage for this type of active ingredient, for which rapid absorption and a rapid pharmacological and vasodilating response are often required.
Thus, serious need continues to exist in this art for preparations of nicorandil exhibiting better stability and rapid bioavailability, not only via the oral route, but also by sublingual administration. Indeed, the ideal pharmaceutical formulation for nicorandil would serve as a protective barrier, to prevent the external humidity from contacting the active ingredient and wherein any excipients would additionally protect the nicorandil from the external humidity, but would also be inert and chemically compatible therewith, to avoid any interactions which may inactivate the product, as in the case of the transesterification indicated above with the triglycerides of the fatty acids and/or the polyglycolized glycerides of aliphatic acids.